The incidence of diabetes world-wide, is expected to reach epidemic proportions by 2025. Progression of diabetic retinopathy often results in diabetic macular edema, which is a consequence of the breakdown of the blood-retinal barrier, increased retinal vascular permeability and leakage of plasma from small blood vessels in the macula leading to loss of central vision. The degree of hyperglycemia and duration of diabetes have been shown to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with an increased risk of mortality from cardiovascular disease (Ismail-Beigi June 29, 2010 Lancet online) as well as with a higher morbidity risk from hypoglycemic episodes. We reason that it is critical to identify a downstream glycemic target that causes increased retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family that is produced by proliferating cells of the islets and promotes regeneration of pancreatic cells. We hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes based on our preliminary studies, which show that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of betacellulin induced retinal hemorrhage and increased vascular permeability in normoglycemic and hyperglycemic mice. A disintegrin and metalloproteinase, ADAM-10 (which plays a role in the cleavage of betacellulin), is increased in the retinae of diabetic mice and humans with diabetic retinopathy. Based on these preliminary results we hypothesize that betacellulin contributes to increased retinal vascular permeability and the pathogenesis of diabetic macular edema. PUBLIC HEALTH RELEVANCE: Retinopathy leading to vision loss is a major long-term consequence for a majority of patients with diabetes (both type I and type II). Increased retinal vascular permeability underlies the pathology of diabetic retinopathy. Under normal physiological conditions the retinal vessels form a tight barrier by virtue of tight junctions that allow a strict control of fluids and solutes that cross the blood-retinal barrier. Loss of this barrier function leads to leaky vessels and macular edema. This project will determine the role of betacellulin and ADAM (disintegrin and metalloproteinase)-10 in the development of retinal vascular leakage. Results from these studies will contribute to a better understanding of the molecular mechanisms that are involved in the formation and maintenance of the blood retinal barrier and may lead to the future development of therapeutic modalities to prevent the devastating vision loss that accompanies diabetes.